Olanzapine has shown to have high activity with regard to the central nervous system and is also useful for the treatment of schizophrenia, schizophreniform disorders, acute mania, mild anxiety states and psychosis.
Various polymorphic and pseudopolymorphic forms, such as solvates, of olanzapine have become known. Some of them are useful for conversion to other desirable forms.
The British patent GB 1 533 235 discloses antipsychotically effective thienobenzodiazepines by a generic formula which also covers olanzapine.
U.S. Pat. No. 5,229,382 discloses olanzapine explicitly. The described process for its synthesis involves a crystallization from acetonitrile.
EP-B-733 635 claims crystalline form II olanzapine, and this polymorphic form is said to be more stable than the material obtained according to U.S. Pat. No. 5,229,382 which is designated “form I olanzapine”. Both the form I and the form II of olanzapine are characterized by e. g. X-ray data. The preparation of the more stable form II of olanzapine is effected by dissolving technical grade olanzapine in ethyl acetate and crystallization from the resulting solution by any conventional process such as seeding, cooling, scratching the glass of the reaction vessel or other common techniques.
WO 02/18390 discloses the monohydrate form I and the dihydrate form I of olanzapine, a process for production thereof and a process for production of form I of olanzapine which comprises the steps of stirring olanzapine monohydrate form I or crude olanzapine or form II of olanzapine in methylene chloride at reflux, cooling, filtering and drying. It is also described that a repeating of the process described in U.S. Pat. No. 5,229,382 Example 1, subexample 4 did not lead to formation of form I of olanzapine.
WO 03/101997 relates to processes for preparation of form I of olanzapine by regulation of the pH-value of the solution.
WO 03/055438 discloses the preparation of form I olanzapine by crystallization from ethanol and subsequent conversion of the obtained ethanol solvate.
U.S. Pat. No. 5,637,584 discloses the (mono)methylene chloride solvate form of olanzapine and a method for its conversion to the polymorphic form I of olanzapine.
EP-B-733 634 discloses three specific solvates of olanzapine, namely the methanol, ethanol and 1-propanol solvates and a process for production of form II olanzapine by drying such a solvate.
WO 03/097650 describes two new mixed solvate forms, the water/methylene chloride solvate and the water/DMSO solvate, methods for preparing them, and their transformation to polymorphic form I.
WO 2004/006933 discloses a process for the preparation of form I olanzapine, as well as various pseudopolymorphic forms, namely the isopropanol solvate, and the acetonitrile/methylene chloride/water and acetonitrile/water mixed solvates of olanzapine, and the polymorphic form A.
However, the prior art processes for preparation of form I olanzapine often do not lead to a satisfactory yield. Moreover, they result in olanzapine having a purity which is not satisfactory for the preparation of pharmaceutical formulations as impurities are present which are difficult to be removed. This is often caused by undesired impurities which are formed upon preparation of precursors and are therefore, upon conversion of the precursors to form I olanzapine, introduced in the final product.
Further, prior art processes often do not allow use of higher temperatures without impairing yield or purity of the form I olanzapine.
Consequently, there is still a need for improved processes to prepare purified olanzapine form I in a satisfactory yield.
Further, there is a need for precursors which allow the easy preparation of polymorphic forms of olanzapine or the conversion to other forms of olanzapine in a high purity.
These problems are solved by the present invention.